Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.
Staphylococcus aureus is a notorious human pathogen that thrives in macrophages. It resides in mature phagolysosomes, where a subset of the bacteria eventually begin to proliferate. How S. aureus acquires essential nutrients, such as amino acids, for growth in this niche is poorly understood. Using...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-08-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013291 |
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| author | Adriana Moldovan Ronald S Flannagan Marcel Rühling Kathrin Stelzner Clara Hans Kerstin Paprotka Tobias C Kunz David E Heinrichs Thomas Rudel Martin J Fraunholz |
| author_facet | Adriana Moldovan Ronald S Flannagan Marcel Rühling Kathrin Stelzner Clara Hans Kerstin Paprotka Tobias C Kunz David E Heinrichs Thomas Rudel Martin J Fraunholz |
| author_sort | Adriana Moldovan |
| collection | DOAJ |
| description | Staphylococcus aureus is a notorious human pathogen that thrives in macrophages. It resides in mature phagolysosomes, where a subset of the bacteria eventually begin to proliferate. How S. aureus acquires essential nutrients, such as amino acids, for growth in this niche is poorly understood. Using a long-term primary human macrophage infection model, we show that branched-chain amino acid (BCAA) uptake mediated by the major transporter BrnQ1 is required by S. aureus for intracellular replication in macrophages and we provide mechanistic insight into the role of BCAAs in the success of intracellular S. aureus. Loss of BrnQ1 function renders intracellular S. aureus non-replicative and non-cytotoxic. The defective intracellular growth of S. aureus brnQ1 mutants can be rescued by supplementation with BCAAs or by overexpression of the BCAA transporters BrnQ1 or BcaP. Inactivation of the CodY repressor rescues the ability of S. aureus brnQ1 mutants to proliferate intracellularly independent of endogenous BCAA synthesis but dependent on BcaP expression. Non-replicating brnQ1 mutants in primary human macrophages become metabolically quiescent and display aberrant gene expression marked by failure to respond to intraphagosomal iron starvation. The bacteria remain, however, viable for an inordinate length of time. This dormant, yet viable bacterial state is distinct from classical persisters and small colony variants. |
| format | Article |
| id | doaj-art-e167b76bca7c4098a70e4aefdd68dd0e |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-e167b76bca7c4098a70e4aefdd68dd0e2025-08-23T05:31:23ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-08-01218e101329110.1371/journal.ppat.1013291Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.Adriana MoldovanRonald S FlannaganMarcel RühlingKathrin StelznerClara HansKerstin PaprotkaTobias C KunzDavid E HeinrichsThomas RudelMartin J FraunholzStaphylococcus aureus is a notorious human pathogen that thrives in macrophages. It resides in mature phagolysosomes, where a subset of the bacteria eventually begin to proliferate. How S. aureus acquires essential nutrients, such as amino acids, for growth in this niche is poorly understood. Using a long-term primary human macrophage infection model, we show that branched-chain amino acid (BCAA) uptake mediated by the major transporter BrnQ1 is required by S. aureus for intracellular replication in macrophages and we provide mechanistic insight into the role of BCAAs in the success of intracellular S. aureus. Loss of BrnQ1 function renders intracellular S. aureus non-replicative and non-cytotoxic. The defective intracellular growth of S. aureus brnQ1 mutants can be rescued by supplementation with BCAAs or by overexpression of the BCAA transporters BrnQ1 or BcaP. Inactivation of the CodY repressor rescues the ability of S. aureus brnQ1 mutants to proliferate intracellularly independent of endogenous BCAA synthesis but dependent on BcaP expression. Non-replicating brnQ1 mutants in primary human macrophages become metabolically quiescent and display aberrant gene expression marked by failure to respond to intraphagosomal iron starvation. The bacteria remain, however, viable for an inordinate length of time. This dormant, yet viable bacterial state is distinct from classical persisters and small colony variants.https://doi.org/10.1371/journal.ppat.1013291 |
| spellingShingle | Adriana Moldovan Ronald S Flannagan Marcel Rühling Kathrin Stelzner Clara Hans Kerstin Paprotka Tobias C Kunz David E Heinrichs Thomas Rudel Martin J Fraunholz Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. PLoS Pathogens |
| title | Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. |
| title_full | Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. |
| title_fullStr | Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. |
| title_full_unstemmed | Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. |
| title_short | Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages. |
| title_sort | inactivation of branched chain amino acid uptake halts staphylococcus aureus growth and induces bacterial quiescence within macrophages |
| url | https://doi.org/10.1371/journal.ppat.1013291 |
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